Abstract Men and women show different incidence and patterns of obesity, which is a major risk factor for diabetes, cardiovascular disease, and other metabolic and reproductive diseases. In mouse models, mice with two X chromosomes have much greater adiposity and dysregulation of lipid metabolism compared with mice with one X chromosome. Thus, the X chromosome encodes factors that contribute to sex differences in metabolism and adiposity. This project aims to understand the metabolic impact of one class of X chromosome genes that are represented differently in nearly all XX and XY cells. These are X genes that escape X inactivation ubiquitously and are expressed from both X chromosomes in XX cells, at a higher level than from the single X chromosome in XY cells. The difference in X gene dosage is hypothesized to give rise to XX vs. XY differences in metabolic disease. Preliminary evidence indicates that one gene escaping X inactivation, histone demethylase Kdm5c, accounts in part for large differences in adiposity and lipid metabolism of mice with one vs. two X chromosomes. The project will investigate the physiological and genomic effects of one vs. two copies of Kdm5c. We will determine the mechanism by which Kdm5c dosage influences adiposity by measuring energy balance, circadian regulation, and related metabolic parameters. We will determine the tissue site(s) of Kdm5c action that account for its effects on adiposity using anatomical and genetic Cre recombinase-mediated strategies. To address the molecular mechanism of Kdm5c dosage effects on adiposity, we will identify which genes are targets of KDM5C histone demethylase activity, resulting in changes in chromatin structure and gene expression. This will inform us about specific gene pathways that are altered by Kdm5c dosage that result in changes in adiposity and metabolism. Because the closely similar Y chromosome paralog Kdm5d appears not to have the same metabolic effects as X-linked Kdm5c, the comparison of the physiological effects, chromatin modifications, and gene expression modulated by Kdm5c and Kdm5d will help to recognize the gene pathways that are regulated by Kdm5c and relevant to metabolism. The results will shed light on fundamental sex differences in obesity and metabolic disease, leading to greater understanding of factors that ameliorate or exacerbate disease.